Manufacture of sulphanilamide



roasted M sa, was i annals a: or soar I donut ct. Wol h N No Brewing. Application some a, lost, strains. lates My present invention relates to a new process tor the manufacture of. sulphanilamide and, more specifically, to a process by which sulphanilamide, or p-aminobenzene sulphonamide, may be manus lectured irom cheap and readily available raw materials, such as the lay-products from the manuiacture oi saccharin. v

in i935, Damask (Deutseh. Med. Wochsch: 61, use, 1935) described the remarkable protection atlorded to mice infected with virulent strains of hemolytlc streptococci by injections of azo dyes containlne the sulphonamide group para to the ace linkage. However, Colebrooh, Buttle, Comb, Ohleara and Kenny (Lancet, 2, 1319, 1323, Dec. 5, 1936) found that these dyes have no in hihiting or bacteriostatic activity on hemolytic streptococci in vitro. By reduction with magncsluinpowder in vacuo, or with sodium formaldehyde sulphoirylate (Lona and Bliss, Journal of the American Medical Association, vol. 108, No. 1, pg. 33), these azo dyes acquired an inhibitory effect in vitro comparable to that of the compound p-aminobenrene sulphonamide, hereinatter referred to as sulphanilamide. They concluded, therefore, as did Treiouel, Nitti and Eovet (@olnntes iendus Soc. Biol. 120, 756, 1935) that these aso sulphonamide dyes have no activity per se but are similarly reduced ,in vivo to the chemotherapeutically active principle, sulphanilamide.

Numerous subsequent reports have confirmed this conclusion and, at the present time, sulphanilamide is mine widely used for peroral and parenteral administration to humans in cases of hemolytic streptococcus conditions such as erysipelas, septicemia, puerperal sepsis, osteomyelitis of streptococcic origin, peritonitis, soarlatina, streptocmcus memnsitis, Ludwics angina, otitis media, etc, as well as in pneumonia, especially where the causative organism is pneumococcus 40 type m. A'tremendousnew field for the use of sulphanilamide has recently'alsobeen opened by the remarkable cures obtained with its use in the treatment of gonorrhea (Bees and Colston, Jourml of the American Medical Association, vol. 5 lot, No. 2, pg. 1855, 1937.)

Heretoiore, sulphanilamide has been manufactored exclusively by the process originally described by Gelgno (Journal fur Praktische Chemie, (2), vol; 77, pg. M2) or by minor modifications 50 thereof. 'i'his process involves reacting N-acetylor N-benzyl-sulphanilic acid with phosphorus pentachloride, converting the resultant N-acetylor N-loenzylsulphouyl chloride to the corresponding amide and subjecting the letterto an acid or obtained. The yields of this process are not satisfactory and the product obtained is usually contaminated by impurities and by-products, which are chemotherapeutically inactive.

I find that sulphanilamide may he obtained in an exceptionally pure state and in quantitative yield by submitting henzamide-p-sulphonarnide to a Hoimann reaction. As is well lrnown to all persons skilled in the art, the Hoimann'reacticn involves the conversion of compounds oi the type REONI-lz to compounds of. the type litl 'll-ls (where R represents an alkyl or an aryl group) by reactinsthe former with a halogen in the presence oi an excess oi tree allrali, or with the chemical equivalent thereof, an aqueous solution of an alkaline or alkaline earth hypohalite in the presence of free alkali. The reaction'may he reps-e sented by the following equation:

C ONE): NHa

' +No0 common +Nsoi+uao 0:;

s 0mm o emu,

the reaction mixtures in each case after the removal oi? all the available chlorine, a quantitative yield of sulphanilamide may be obtained. A

sinylereorystallization from water yields a prod- 7 not suitable for human consumption.

It is not the purpose of mm invention to limit the manufacture oi. sulphanilamide to benzamidepvsulphonamide obtained from any specified raw materials. Obvious means of preparing this intermediate will occur to any person smiled in the art. However, the by-products obtained in the manufacture of saccharin may cheaply and simply he convertw. to benzamide-p sulphonamide and are, therefore, of importance in this process.

German Patent #353717 describes the preparation of benzamide-psulphonamide from benzoicp-sulphonic acid, or a salt thereof, by reacting the latter with phosphorus pentachloride to form benzoyl chloride-p-sulphonylchloride, then with ammonia. to form the diamide. Benzoic-p-sulphonic acid may readily be obtained by the oxida 5 tion of toluene-p-sulphonic acid or toluene-psulphonyl chloride (Remsen, Annalen, 1'78, 284, 290), by-products of the manufacture of sac charin.

German Patents #96,125 and #103,298 describe 1 thepreparation of benzamide-p-sulphonamide 'by the anfi'nonolysis of ethyl benzoate-p-sulphonyl chloride. The latter may be obtained by benzoic acid are obtained (Remsen, Annalen, 1'18,

297). p-Sulphonamidobenzoicacid is then esterified in the usual manner, preferably by the 25 use of an alkylating agent, such as a dialkyl sulphate, an alkyl halide, an alcohol in the presence of a condensing agent such as dry hydrochloric acid gas or a dehydrating agent such as concentrated sulphuric acid, etc."

30 Alkyl-p-sulphonamidobenzoate may be converted to benzamide-p-sulphonamide by am-.

monolysis. By reacting ethyl-p-sulphonamidobenzoate with an excess of dry ammonia gas at normal orincreased pressure in an autoclave, a 35 quantitative yield of ben zamide-p-sulphonamide is obtained. By reacting ethyl-p-sulphonamidobenzoate with concentrated aqua ammonia at ordinary temperatures, benzamide-p-sulphonamide is obtained in yields of 65% to 85% of the 4o theoretical, depending on the concentration of the ammonia and the reaction time. The remaining 15% to 35% of the ethyl-p-sulphonamidobenzoateis hydrolyzed to the ammonium salt of -sulphonaminobenzoic acid, which is 45 readily s luble in water and may thus be separated from the substantially insoluble benzamide-p-sulphonamide by filtration and returned to the process.-

One of the difiiculties encountered in the pres- 50 cut processes of manufacturing saccharin is the separation of the para and the ortho isomers of the crude toluene sulphonyl chloride. If this separation is not attempted but the combined to-- luene sulphonamides are converted to the corre- 55 sponding ethyl sulphonamidobenzoates; as described above, an excellent means is provided of obtaining both saccharin and benzamide-p-sulphonamide in a single operation. The conversion of ethyl-o-sulphonamido-beno0 zoate to saccharin by reaction with ammonia is rapid and quantitative (German Patent #103,- 298). The combined ethyl sulphonamidobenzoates are reacted with aqua ammonia, and the reaction mixture is then diluted and filtered from 65 the insoluble benzamide-p-sulphonamide. The

filtrate now contains the ammonium salts of saccharin and p-sulphonamidobenzoic acid in so1utlon. Thesaare separated by fractional precipitation with mineral acid, as described in German 70 Patent #64524. p-Sulphonamidobenzoic acid precipitates out first, is filtered of! and returned to the process. Saccharin-then precipitates out state of great purity.

*"*"*on-furtheracidification, ingood, yield and in a 7 The following examples are intended to define and illustrate this invention but in no way'limit it to the reagents, proportions or conditions de-e scribed therein.

. Example I 20.0 kgs. of.benzamide-p-sulphonamide. is dis- 5 solved in 160.0 liters of a 5% (1.3 B.) solution of caustic soda in the cold. and 55.0 liters of 14% sodium hypochlorite solution is added. The solution is .then heated gradually to 40 0., and sulphur dioxide is passed into it until a negative re action to potassium iodide-starch paper is obtained. The reaction mixture is then neutralized to' phenolphthalein with 42 B. sulphuric acid,

and the copious precipitate of sulphanilamide which forms on standing overnight is filtered off. After a single recrystallization from water, 15.8 to 16.4 kgs. of pure sulphanilamide is obtained (92% to 95% of the theoretical, based on the benzamide-p-sulphonamide consumed).

Example II 17.5 kgs. of technical p-toluene sulphonamide is suspended in a cold solution of 50.0 kgs. of potassium dichromate and 75.0 kgs. of 66 B. sulphuric acid in 125.0 liters of water. The mixture is warmed slightly and mixed until the reaction commences and the amide goes into solution. After ashort time, separation of. p-sulphonamidobenzoic acid commences and at the end of two hours, the entire reaction mixture is -a thick magma. The heating is now,discontinued, the reaction mixture is cooled to room temperature and filtered. The precipitate of p-sulphonamidobenzoic acid on the filter is then thoroughly washed until the washwater is free of chromium.

The filter cake of p-sulphonamidobenzoic acid is now dissolved in 80.0 liters of 5% (.7.3- B.) solution of caustic soda and 15.4 kgs. of dlethyl sulphate is added. Thef mixture is stirred until the diethyl sulphate has. completely disappeared 40 and for an hour thereafter. I

The precipitate of ethyl-p-sulphonamidobenzoate is now filtered 01! and added to 50.0 liters of 27 B. aqua ammonia. After standing for 24 hours at room temperature, 100.0 liters of water 45 is added, and the precipitated benzamide-p-sulphonamide is filtered on. On acidifying the filtrate with 42 B. sulphuric acid, p-sulphonamidobenzoic acid is precipitated, filtered on, and returned to the process. 1

The benzamide-p-sulphonamide thus obtained is converted to sulphanilamide as described in ExampleI.

. Example-III J 22.0 kgs. of technical p-toluene sulphonamide is dissolved in-12.5 kg. of 38% (35.2 B.) caustic soda and 60.0 liters of water at a temperature not exceeding 35 0., and 40.0 kg. of potassium permanganate is added to the solution, with conmy 42 B. sulphuric acid is added to the combined solution until the reaction is faintly acid to Congo red. About 5.0 kgs. of unchanged p toluene sulphonamide is precipitated, filtered oil! and re- 2 turned to the process. To the filtrate is added 15.4 kgs. of diethyl sulphate.v The mixture is stirred until the diethyi sulphate has completely disappeared and for an hour thereafter.

- The precipitate of ethyi-p-sulphonamidobenzoate thus obtained is converted to benzamide-p-' sulphonamide as described in Example 11.

Example IV 10.0 kgs. of toluene is added in the course of four hours to 15.0 kgs. of chlorsulphonic-acid at C. The mixture is then stirred for two hours at 5 to C. and. poured on 10.0 kgs. of ice and 10.0 kgs. of water.

The resultant mixture of 10.0 kgs. of o-toluene sulphonylchloride' and-7.5 kgs. of p-toluene sulphonyl chloride is' decanted from the aqueous layer and added to 15.0 kgs. of 27 B. aqua ammonia in the course of four hours. The mixture is stirred at a temperature of 30-35 C. for two is converted'to sulphanilamide as 35 Example I.

precipitated.

hours, washed free of ammonium chloride with 5.0 liters of water and filtered. There is thus obtained about 14.0 kgs. of a mixture containing 57% of o-toluene sulphonamide and-43% of ptoluene sulphonamide.

17.5 kgs. of the mixture of toluene sulphonamides is treated as described in Example 11. The filtrate from the precipitate of benzamldep-sulphonamide is fractionally precipitated with 42 B. sulphuric acid as described in German Patent #64524. p-Sulphonamidobenzoic acid is precipitated first, filtered 011 and returned to the process. On further acidification, saccharin is The benzamide-p-sulphonamide thus obtained described in amide which comprises reacting benzamide-psulphonamide with a halogen in the presence of alkali metal hydroxide. I

3. A process for the manufacture of. sulphaniiamide which comprises reacting vbenzamide-psuiphonamide with an alkali metal hypohalite 'in the presence of an alkali metal hydroxide.

4. A process for themanuiacture ofsulphanilamide which comprises reacting an ester of p-sulphonamidobenzoicacid with ammonia and submitting the resultant benzamide-p-sulphonamide to a Hofmann reaction.

5. A process for the manufacture of sulphanii-' amide which comprises reacting ethyl-p-sulphon- I amidobenzoate with ammonia and submitting the Y resultant benzamide-p-sulphonamide to'a Hofmann reaction.

6. As a step in a process for the manufacture p-sulphonamidobenzoic acid.

v JONAS KAMLE'I'.

.of sulpanilamide, the ammonolysis-ot an ester of 

